Pain is a significant and costly healthcare problem, and is the most common reason patients seek medical care. Pain may be acute or chronic. Examples of acute pain include post-surgical pain and pain due to traumatic injuries. Chronic pain is generally more difficult to treat, and can be associated with any number of causes. For example, chronic pain may be associated with the inflammation of joints, tendons, nerves, muscle, and other soft tissues, with diseases such as cancer, or with injuries to the nervous system (“neuropathic” pain).
There is particular interest in developing improved therapies for the treatment of neuropathic pain, which is a challenging medical condition to treat as it can involve both the peripheral and central nervous systems. Neuropathic pain often persists following viral infection, trauma, administration of certain medications, or a metabolic insult. Nerves that remain intact following such as disease or injury can become hyperactive, causing pain even in the absence of a direct stimulus. Neuropathic pain is often described as a burning, excruciating pain and may never resolve. The severity of the pain is in part due to the nerve endings near the surface of the skin. Unfortunately, neuropathic pain is generally insensitive to administration nonsteroidal anti-inflammatory drugs, which are often successfully prescribed for the treatment of acute pain.
There are several types of neuropathic pain. The more common types include post-herpetic neuralgia, neuropathic pain related to human immunodeficiency virus (HIV)-associated neuropathy, neuropathic pain associated with diabetic neuropathy, and trigeminal neuralgia. Post-herpetic neuralgia is chronic, mild to severe burning pain on the surface of the skin that develops in some patients after healing of shingles (herpes zoster). Both the HIV infection, as well as HIV medications, are associated with the development of neuropathy and neuropathic pain. This pain typically affects the feet and hands, and is commonly referred to as neuropathic pain related to HIV-associated neuropathy. Diabetic neuropathy is a common complication of diabetes mellitus, and can lead to amputation. Peripheral diabetic neuropathy is typically characterized by pain, weakness, and reduced or lost sensation in the feet. Trigeminal neuralgia is a disorder of the trigeminal nerve, which causes episodes of intense, stabbing, electric shock-like pain in the areas of the face in which nerve endings are located (e.g., the lips, eyes, nose, scalp, forehead, upper jaw, and lower jaw). Other types of diabetic neuropathy include autonomic neuropathy, proximal neuropathy, and focal neuropathy.
In addition to these common types of neuropathic pain, there are numerous medical conditions that are associated with neuropathic pain. These include traumatic nerve injury, stroke, multiple sclerosis, epilepsy, spinal cord injury, and cancer.
Current therapies for neuropathic pain are limited, often involving the administration of multiple medications with the understanding that pain relief will not be complete and the quality of life may not be restored. These therapies may require frequent dosing, can be associated with undesirable systemic side effects, and typically provide unsatisfactory relief. Therefore, there remains a need for a therapeutic option developed specifically for neuropathic pain that provides sustained relief while minimizing the potential for systemic side effects and drug-drug interactions.
Capsaicin (8-methyl-N-vanillyl-6Z-nonenamide) and “synthetic” capsaicin (N-vanillyl-nonenamide) are disclosed as analgesics in U.S. Pat. No. 4,313,958 to LaHann. Analgesic activity of capsaicin has also been discussed in the chemical and medical literature, including Yaksh, et al. (1979) Science 206:481-483. Capsaicin is derived from the plants of the solanaceae family, and is the purified extracted alkaloid from red chili peppers. Capsaicin has been found to relieve pain by reducing substance P, which is found at nerve endings and is involved in transmitting neuralgic and arthritic pain signals to the brain. Pain relief is not instantaneous after application as it is the cumulative depletion of substance P over a period of weeks that brings the full effect.
Low-concentration capsaicin topical creams have been used for years to treat neuropathic pain, but their use has been limited because they are inconvenient to apply and must be applied at regular intervals throughout the day, even then achieving only modest pain relief at best. Unfortunately, capsaicin is a potent skin irritant, and the application of capsaicin itself can cause burning pain and hyperalgesia, exacerbating the pain being treated. This intense initial burning effect usually diminishes after the first few days of application and in most cases disappears with time and continued use; the initial side effects are sufficiently severe, however, to significantly impact on patient compliance, thus diminishing the overall therapeutic value of capsaicin as an effective treatment for pain.
In order to minimize the initial burning sensation associated with the topical administration of capsaicin formulations, the skin can be pre-treated with an anesthetic agent. Two-step therapy can be cumbersome for chronic users, however. Furthermore, because capsaicin is poorly soluble in aqueous solvents, any capsaicin formulation used in this context will have a relatively low concentration of the drug, again requiring frequent application as noted above.
Several patents describe topical capsaicin formulations and are of background interest with respect to the present invention: U.S. Pat. No. 4,812,446 to Brand describes an analgesic composition comprising capsaicin or a capsaicin analogue and an analgesic selected from the class of non-steroidal anti-inflammatory, antipyretic and analgesic drugs. U.S. Pat. No. 4,997,853 to Bernstein describes a 0.01-1.0 wt % capsaicin formulation containing 0.5-25 wt % of a topical anesthetic. U.S. Pat. No. 5,962,532 to Campbell et al. describes the use of a 0.01-10 wt % capsaicin formulation to treat pain. Anesthesia is first provided to the site where the capsaicin is to be administered, for example, by epidural regional anesthesia. U.S. Pat. No. 6,248,788 to Robbins et al. describes a 5-10 wt % capsaicin formulation, accompanied by a regional anesthetic, preferably by means of a somatic or neuraxial block. See also, Robbins et al. (1998) Anesth. Analg. 86:579-583. U.S. Pat. No. 5,869,533 to Holt describes a polymeric formulation of 0.00125-1 wt % capsaicin together with a plant extract to neutralize the discomfort resulting from the application of capsaicin. Although directed towards providing improved anesthesia instead of pain relief, U.S. Pat. No. 6,299,902 to Jun et al. describes a two-phase liquid composition comprising a local anesthetic agent, a first melting point depressing agent, for example capsaicin, and a second melting point depressing agent, which is a liquid, more specifically an alcohol.
Despite the advancements in the art, there remains a need for more effective pain-relieving formulations. An ideal formulation, particularly for the treatment of neuropathic pain, would contain higher levels of capsaicin than previously possible but not cause the discomfort and burning associated with capsaicin formulations of the prior art.